Detecting aneurysmal instability by linking imaging and genetics

Rupture of an intracranial aneurysm (IA) causes aneurysmal subarachnoid
hemorrhage (ASAH), a severe form of stroke accounting for the highest
patient-related costs across stroke-types, and for comparable life years lost
to ischemic stroke. Upon detection of an IA, invasive surgical or endovascular
intervention (clipping or coiling) can prevent rupture. However, interventions
come with risk of complications and predicting which IAs are prone to rupture -
and thus for which IAs intervention has favorable benefit-to-risk ratio -
remains challenging. As a result, only a minority of IAs is treated, leaving
many patients at risk of rupture.

The best surrogate for IA rupture is aneurysmal instability (growth and/or
shape change), but this requires long follow-up with intervals of typically
five years during which rupture may occur. Having an unruptured IA without
knowing whether it may someday rupture causes a psychological burden in these
patients. To allow fast prediction of rupture, single time-point aneurysmal and
patient characteristics that correlate with rupture can be used to assess
rupture risk. However, their predictive relevance has been debated as most
ASAHs are the result of rupture of aneurysms with estimated low rupture risk
(i.e. low PHASES score, the most commonly used rupture risk prediction).

Hemodynamic characteristics play a role in aneurysmal instability and rupture.
Small changes in aneurysm shape can have significant impact on flow, and wall
shear stress (WSS) can in turn cause vascular remodeling and IA destabilization
Low pulsatility, blood flow instability, and aberrant WSS contribute to IA
destabilizing and/or rupture. A recent UMCU study showed that 4D flow MRI on 7
Tesla can be used for accurate quantification of wall shear stress, flow,
velocity, and pulsatility index in human IAs in vivo. However, these
measurements rely on the application of additional magnetic field gradients and
typically suffer from long acquisition times and low signal-to-noise ratio.
Building on UMCU*s expertise in gradient hardware, we will boost MRI flow
measurements by using a novel strong-gradient head insert coil (funded by
Health Holland) which significantly improves the efficiency of translational
motion (diffusion or flow) encoding. Having only been applied to diffusion MRI,
this first use of strong gradients for flow MRI should lead to previously
unattainable signal-to-noise levels, accurate quantification of slow-flow
velocities, and short acquisition times.

Cellular changes occur prior to IA formation and during periods of aneurysmal
instability. A dynamic process of vascular remodeling and inflammation leads to
thinning and disruption of vascular layers, thereby destabilizing the vascular
wall. Smooth muscle cells and endothelial cells have distinct roles in
aneurysmal stability, complicating the detection of cellular markers and
necessitating a cell-type specific approach. Recently, single-nucleus RNA
sequencing has become available to detect gene expression changes on a cellular
level. It was shown that this technique can detect expression differences in
arterial tissue that cell-types can be distinguished in IAs. We will use
single-nucleus RNA sequencing to obtain expression patterns per cell-type.

Cellular and hemodynamic characteristics are intrinsically interrelated:
Arterial geometry affects gene expression in vascular endothelial cells,
including actin cytoskeletal organization, and inflammation. Pulsatility is
associated with endothelial cell stress and with the expression of adhesion
molecules. Here, we will tackle technical limitations in imaging and genomics
to achieve unprecedented characterization of aneurysmal rupture risk.

We hypothesize that the joint analysis of hemodynamic and cellular markers can
characterize IA rupture risk with precision that cannot be achieved by studying
either component separately.

This project will develop single time-point markers of IA rupture risk, with
the goal to detect IAs at high risk of rupture earlier and reduce burden of
ASAH. To achieve this goal, we will be the first study to include markers of
both 1) hemodynamic processes (from imaging) and 2) cellular characteristics
(from biopsy and blood) in the same IA. By retrospective correlation with
aneurysmal stability from existing longitudinal data, we aim to 1) gain better
understanding of the interplay between hemodynamic and cellular processes
underlying rupture risk, and 2) identify markers that can maximally
discriminate between high and low rupture risk IAs. Identifying non-invasive
markers from imaging and blood help pave the way to our long-term goal of
prospective and early prediction of ASAH.

Primary Objective:
Identify markers that distinguish between high and low rupture risk IAs.

Secondary Objective(s):
• Gain insight in the hemodynamic and cellular processes underlying IA rupture
risk.
• Determine the interrelatedness of hemodynamic and cellular markers in IA.
• Test if cellular markers that explain differences in surrogate markers for
rupture risk of IA can be detected in blood.

This study is a cross-sectional cohort study. The population consists of all
patients of age 18 years or older with an unruptured IA who need surgical
clipping to treat the IA and who are admitted to the UMC Utrecht. Within this
population we will study which genetic and hemodynamic parameters explain
differences in surrogate markers for rupture risk (being IA size, and PHASES
score).

The duration of the study is 3 years.

Participating will cost the patients time (one hour in total). The risk
associated with the study are minimal. Undergoing an MRI scan is safe. the
intracranial aneurysm biopsy will be taken after placing a clip and
confirmation by the neurosurgeon that the aneurysm has been completely blocked
off from the circulation. The neurosurgeon decides during surgery whether
taking a biopsy is safe.